Blast-induced traumatic brain injury (blast-TBI) is a leading cause of death and disability in soldiers and veterans involved in recent wars in the Middle East, and in civilians exposed to terrorist acts. It is generally accepted that a blast wave can affect the brain via both a direct transcranial path and by an indirect transthoracic/transvascular path. Cellular and molecular mechanisms involved in each path are poorly understood. We hypothesize that the neurological consequences of direct vs. indirect blast injury will be significantly different, with subarachnoid hemorrhage and injury to raphe neurons predisposing to post- traumatic stress disorder (PTSD)-like symptoms predominating with direct injury, versus edema and perivascular inflammation predominating with indirect injury. We recently developed a unique device designed to deliver a blast wave exclusively to the cranium - a Cranium Only Blast Injury Apparatus (COBIA), allowing study of the effects of a blast wave on the brain independent of the effects due to the transthoracic/transvascular mechanism. The most important insight to emerge from this work is that a blast wave that impacts the cranium tends to injure tissues at density boundaries, especially the cerebrospinal fluid (CSF)-brain density boundaries, predisposing to subarachnoid hemorhage and to injury to periventicular neurons, with significant involvement of the dorsal raphe nucleus, a critical source of serotoninergic (5-HT) innervation in forebrain structures. New preliminary work for this proposal included the development of a Thoracic Only Blast Injury Apparatus (TOBIA) to allow study of this mechanism of injury, and to explore specific involvement of the vasculature and its role in altered BBB permeability and perivascular inflammation. Preliminary data for this proposal show that the sulfonylurea receptor 1 (SUR1)-regulated NC(Ca-ATP) channel, which we discovered plays a central role in non-blast-induced traumatic and ischemic CNS injuries, is upregulated after exposure of rats to blasts from COBIA and TOBIA. Here, in Specific Aim 1, we will elucidate and compare responses of the brain to: (i) direct delivery of the blast wave to the brain via cranial exposure vs. (ii) indirect delivery of a blast wave to the brain via transthoracic/transvascular exposure vs. (iii) combined delivery via total body exposure. We will determine the early activation of the mechano-sensitive transcription factors, specificity protein 1 (Sp1) and nuclear factor kappaB (p65), and the time-course and cellular localization for the cell death molecules, SUR1, transient receptor potential melastatin 4 (TRPM4) and caspase- 3, using qPCR, in situ hybridization, immunoblots and immunohistochemistry. In Specific Aim 2, we will evaluate the effect of the SUR1-selective blocker, glibenclamide, on blast-induced secondary injury involving SUR1. We will assess the effect of glibenclamide, administered 1 hour after injury, on early vestibulomotor and later cognitive and neuropsychological function, and on tissue markers of cell death, neurodegeneration, inflammation and 5-HT innervation in forebrain structures. There is an urgent need to develop effective pharamacotherapies for victims of blast-TBI, to block secondary injury responses that are induced by a blast wave, including subarachnoid hemorrhage-induced inflammation of the cortex, altered BBB permeability, and delayed neuropsychological disorders. We anticipate that the successful completion of the proposed studies will advance our understanding of pathophysiological mechanisms of brain injury induced by blast, will establish the therapeutic potential of glibenclamide in blast-TBI, and will elucidate novel findings that may link blast- TBI to PTSD-like symptoms.